The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Zhoux, Xiyou; Davis, Deborah R.

doi:10.1074/jbc.m608055200

Cited by 33 publications

(51 citation statements)

References 51 publications

(44 reference statements)

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“…These data fit with recent evidence challenging the role of the renin enhancer in the regulation of renin expression in vivo. 22 On the other hand, the mouse renin enhancer was shown to be critical for the salt-dependent control of renin synthesis in transgenic mice. 23 Thus, the role of the renin enhancer in the regulation of renin gene expression in vivo remains to be further clarified.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ Is Involved in the Control of Renin Gene Expression

et al. 2007

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Abstract-Based on the presence of a functional retinoic acid receptor/retinoid X receptor transcription factor binding sequence (hormone-responsive element) in the renin gene enhancer and on the fact that the peroxisome proliferatoractivated receptors (PPARs) bind to DNA as heterodimers with retinoid X receptors, we speculated that PPARs are involved in the regulation of renin gene expression. To test this hypothesis, we used the human renin-producing cell line CaLu-6. Endogenous or pharmacological PPAR␥ agonists (unsaturated fatty acids and thiazolidinediones, respectively) stimulated renin gene expression. Surprisingly, we found that PPAR␥ targets a palindromic repeat with a 3-bp spacer (Pal3) in the proximal human renin promoter. Thus, renin is the first gene described with a functional Pal3 sequence. PPAR␥ agonists also stimulated renin gene expression in cultured native juxtaglomerular cells, which are the main source of renin in vivo. In summary, PPAR␥ was identified as a novel intracellular mediator involved in the upregulation of renin transcription. Key Words: basic science Ⅲ gene expression/regulation Ⅲ hypertension (kidney), renin Ⅲ cell signaling P lasma renin is aspartyl protease, produced by the juxtaglomerular (JG) cells of the kidney. Renin is the ratelimiting factor of the renin-angiotensin-aldosterone-system, which is of fundamental importance to the regulation of blood pressure. 1 Therefore, the mechanisms involved in the control of the renin gene are extensively characterized. An enhancer sequence, which activates transcription in a position-and orientation-independent manner, was identified in the 5Ј-flanking region of the mouse renin gene. 2 The renin enhancer contains an Ϸ50-bp-long region, which attracts much attention because it is involved in the regulation of renin transcription by virtually all cues tested until now. [2][3][4][5][6][7] A direct repeat 5Ј-AGGTCA-3Ј was identified within the 50-bp enhancer sequence. 7 This direct repeat is principally known as the hormone-responsive element (HRE), because it is the consensus DNA-binding site for the nuclear hormone receptor superfamily. 8 The nuclear hormone receptors represent ligand-activated transcription factors, which are the intracellular docking stations for membrane-permeable bioactive substances, such as corticoids, retinoids, vitamin D3, thyroid hormones, and free fatty acids. Retinoic acid (vitamin A) was found to stimulate renin transcription through retinoic acid receptor-␣ and retinoid X receptor (RXR)-␣. 7 Mice lacking the vitamin D3 receptor have elevated renin mRNA levels, and vitamin D3 inhibits renin promoter activity. 9 Thyroid hormone was also found to regulate renin transcription. 10 On the other hand, aldosterone does not influence renin transcription but stabilizes renin mRNA. 11 Thus, peroxisome proliferator-activated receptors (PPARs) remained as the last nuclear hormone receptor subfamily, which has not been studied for its impact on renin transcription. Such an effect is feasible because PPARs bind to DNA as ...

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Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ Is Involved in the Control of Renin Gene Expression

et al. 2007

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“…[1][2][3][4][5] It has been reported recently that deletion of the mouse 6 or human 7 enhancer in genetically engineered mice leads to a marked reduction in renin in renal juxtaglomerular (JG) cells, which are the classical source of circulating renin. Telemetry studies of mouse renin enhancer knockout (REKO) mice revealed normal diurnal rhythm of blood pressure, but at a mean 9 mm Hg lower level.…”

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confidence: 99%

Renin Enhancer Is Crucial for Full Response in Renin Expression to an In Vivo Stimulus

et al. 2007

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Abstract-We showed recently that deletion of a strong enhancer located 2.7 kb upstream of the renin gene in mice produces a strain with mild hypotension and salt-sensitivity. Here we set out to compare responses in renin expression in kidney and extrarenal tissues in these "REKO" mice. REKO and wild-type mice were placed on a low NaCl/enalapril regimen for 1 week, and then Ren-1 c mRNA and renin enzyme activities were measured in tissues and plasma. In untreated REKO mice, renin and Ren-1 c mRNA were reduced significantly in kidney, submandibular gland, adrenal, heart, and brain. In situ hybridization indicated a marked reduction in Ren-1 c mRNA in juxtaglomerular cells and granular ducts of submandibular gland. After the chronic stimulus response in renal Ren-1 c mRNA in REKO mice was blunted by 54% compared with wild-type mice, and was accompanied by almost complete exhaustion of renin stores. Response in plasma renin was blunted by 47%, this being mirrored in heart (54% decline), in which renin is derived mostly from the bloodstream. In adrenal a 55% reduction was seen. These data are consistent with inability of REKO mice to adequately replenish renal renin stores during chronic stimulation of renin secretion. In conclusion, the renin enhancer is critical for replenishment of renin stores and response in renin to a chronic in vivo stimulus. Key Words: renin gene expression Ⅲ enhancer Ⅲ knockout mouse Ⅲ low sodium diet Ⅲ angiotensin converting enzyme inhibitor Ⅲ renin mRNA Ⅲ renin enzymatic activity Ⅲ kidney Ⅲ extrarenal renin expression L ocated far upstream of the renin gene of various species is a strong enhancer. 1-5 It has been reported recently that deletion of the mouse 6 or human 7 enhancer in genetically engineered mice leads to a marked reduction in renin in renal juxtaglomerular (JG) cells, which are the classical source of circulating renin. Telemetry studies of mouse renin enhancer knockout (REKO) mice revealed normal diurnal rhythm of blood pressure, but at a mean 9 mm Hg lower level. 6 This was partly normalized by a high NaCl diet. The REKO mice exhibited reduced locomotor activity, normal baroreflex sensitivity, 6 and a blunted cardiovascular response to stress. 8 Here we investigate the response in renin expression of our REKO mice to a strong physiological challenge, namely a low NaCl diet coupled with administration of the ACE inhibitor enalapril, which reduces angiotensin II and thus feedback inhibition of renin secretion. As part of this we measured renin and Ren-1 c mRNA in renal and extrarenal tissues and performed in situ hybridization. Our findings highlight a critical role of the renin enhancer in physiological regulation of renin expression and thus physiological sequelae. Materials and Methods Generation of REKO MiceThe production of REKO mice was as described previously. 6 The experiments described herein were approved by the University of Sydney Animal Ethics Committee. REKO and wild-type (WT; C57BL6) mice were housed in accordance with SPF regulations. In Situ HybridizationReni...

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“…Renin levels in mice are much higher than in humans suggesting that the enhancer may be more active in mice. Although the enhancer is conserved among mammalian renin genes, there are some critical differences that markedly influence the level of enhancer activity (Zhou et al, 2006). Several decades ago, the observation that renal renin secretion responds to osmotic change either in renal perfusate or in the microenvironment of juxtaglomerular cells, prompted many investigations.…”

Section: Reninmentioning

confidence: 99%

Intrarenal renin–angiotensin system

Rosivall

2009

Molecular and Cellular Endocrinology

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The Human Renin Kidney Enhancer Is Required to Maintain Base-line Renin Expression but Is Dispensable for Tissue-specific, Cell-specific, and Regulated Expression

Cited by 33 publications

References 51 publications

Peroxisome Proliferator-Activated Receptor-γ Is Involved in the Control of Renin Gene Expression

Peroxisome Proliferator-Activated Receptor-γ Is Involved in the Control of Renin Gene Expression

Renin Enhancer Is Crucial for Full Response in Renin Expression to an In Vivo Stimulus

Intrarenal renin–angiotensin system

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